Brivaracetam in treating epileptic encephalopathy and refractory focal epilepsies in patients under 14 years of age

Objectives To analyze the efficacy and safety of Brivaracetam in pediatric patients with epileptic encephalopathy or unresponsive focal epilepsy. Materials & Methods This retrospective study included eight pediatric patients with EE or unresponsive focal epilepsy. Inclusion criteria: (1) ≤14 years, (2) history of refractory epilepsy, (3) at least one month of continuous therapy with BRV, and (4) at least six months of follow-up. Exclusion criteria: (1) variation of concomitant antiepileptic drugs during the previous and/or subsequent four weeks of the BRV introduction, (2) levetiracetam in therapy, (3) epilepsy secondary to the progressive cerebral disease, tumor, or any other progressive neurodegenerative diseases, and (4) a status epilepticus a month before screening or during the baseline period. The efficacy of BRV was defined as ≥50% of seizure frequency reduction at the end of the follow-up, compared to baseline. Results: All patients showed ≥50% seizure frequency reduction, of whom 37.5% were seizure-free, 25% had a frequency reduction of ≥75%, and 37.5% had frequency reduction of ≥ 50%. All patients with an epilepsy onset >12 months and epilepsy duration of ≤6 years were seizure-free. The maximum effect was achieved at 2 mg/kg/day, and focal seizures revealed a better response than epileptic encephalopathy. A remarkably positive effect of the Brivaracetam was noticed in patients with encephalopathy regarding the status epilepticus during sleep; however, no relevant side-effects were noted. Conclusion: Brivaracetam was an effective and well-tolerated treatment in pediatric patients with epileptic encephalopathy or unresponsive focal epilepsy, especially for the epilepsy onset >12 months and the epilepsy duration ≤6 years. The total effect was not dose-dependent. Brivaracetam could represent an indication of encephalopathy regarding the status epilepticus during sleep.


Introduction
In the last 20 years, due to the high prevalence of therapy-resistant epilepsy, there has been a need to develop newer antiepileptic drugs with a more recent mechanism of action such as synaptic vesicle glycoprotein 2A, a transmembrane glycoprotein, and galactose transporter (1)(2)(3)(4).
Brivaracetam is a selective, high-affinity ligand for synaptic vesicle glycoprotein 2A, approved as adjunctive therapy and monotherapy for the treatment of focal seizures in patients aged ≥4 years in the United States and for focal seizures with or without secondary generalization in patients aged ≥4 years in the European Union (5,6). Several randomized controlled trials have been conducted in the adult population, revealing promising data on the efficacy and tolerability of Brivaracetam with ≥50% responder rate (7)(8)(9)(10)(11)(12)(13).
The results obtained from pre-marketing trials were confirmed by subsequent postmarketing studies addressing adult patients or a mixed population with a small group of pediatric subjects with different epileptic conditions, including unresponsive focal epilepsy, refractory status epilepticus (14)(15)(16)(17)(18)(19)(20)(21), generalized epilepsies, absence status epilepticus (22), and epileptic encephalopathies (23). The literature is limited on exclusively pediatric population with unresponsive epilepsy, and the existing data come from a phase IIA study and a retrospective study (24,25

Materials & Methods
In this study, eight patients with epileptic encephalopathy or unresponsive focal epilepsy were retrospectively selected from a cohort of We considered a dependent variable (namely age at epilepsy onset, duration of epilepsy before the Brivaracetam, etiology, seizure and epilepsy type, and seizure frequency) as "likely influencing" the independent variable (seizure frequency) if the difference between the two arms of the dependent variable was more than 25%.
According to the U.S. Food and Drug Administration definitions (28) the appearance of adverse events was also checked. Patients or their legal guardians submitted written informed consent.

Results
Of the twenty-five patients initiating Brivaracetam therapy, eight met our inclusion/exclusion criteria; however, none of the patients withdrew from the treatment. Table 1 summarizes the participants' characteristics at the baseline and at the end of the follow-up phase.
The study population included four males and four females. The median age of this cohort was 13 years (ranging from eight years and four months -14 years), and their median age for epilepsy onset was seven months (ranging from 1-96 months). At a median 8-month follow-up (range 6-11 months), the overall response rate (≥50% seizure frequency reduction) was 100% (8/8 patients). Of the participants, three patients were seizure-free (37.5%), two cases had a frequency reduction of ≥ 75% (25%), and three patients had a frequency reduction of ≥ 50% (37.5%) (Fig. 1). In all patients, the maximum benefit of Brivaracetam was achieved at 2 mg/kg/day. No further benefit was reported when the daily dose was increased by 3 mg/kg/day and 4 mg/kg/day. As shown in Fig. 2, patients with focal seizures tended to respond better (response rate 87.5%) than the patients with epileptic encephalopathy (response rate 62.5%). Table 2, patients with an epilepsy onset > 12 months and duration of epilepsy ≤ 6 years were seizure-free at the last follow-up phase, compared to those with an epilepsy onset ≤ 12 months and duration of epilepsy > 6 years (responder rate of 60%).

As shown in
No differences was observed between the seizure frequency before the Brivaracetam (response rate: ≤ weekly 81.25%, daily 68.25%) and etiology (response rate: genetic etiology 75%, structural etiology 81.25%).
In addition to the seizure-freedom, a quick and remarkable improvement of the electroencephalogram and behavior was noticed in a patient with encephalopathy regarding status epilepticus during sleep (Fig. 3). Relevant adverse events were reported in none of the patients.

Discussion
Although regulatory trials (7)(8)(9)(10)(11)(12)(13)  Only two studies have exclusively addressed the pediatric population (24,25). The first was a phase IIA, open-label, single-arm, multicenter trial (24), and the second one was a retrospective multicenter study (25). In these two studies, the efficacy and tolerability of the adjunctive treatment with Brivaracetam were compared to the previous studies on the adult population, with a response rate of ≥50%. They reported the most common treatment-related adverse events as somnolence and decreased appetite; however, the studies had some bias.
In the phase II trial, the Brivaracetam was administered only for three weeks. Our study confirmed the efficacy of previous data showing a response rate > 50% (Fig. 1). The best response was observed in patients with an epilepsy onset > 12 months and duration of epilepsy ≤ 6 years (100% seizure-free) ( Table 2). Moreover, better response was achieved in drug-resistant focal epilepsies (87.5%) as compared to patients with EE (62.5%) (Fig. 2) On the other hand, the advantages of a retrospective study was that the findings cannot be predetermined, that the evaluations are based on existing data sources in which both exposure and outcomes are available, and that the findings cannot be tailored to the data collected for a specific drug.
Prospective controlled studies on large homogeneous population are required to evaluate the long-term effectiveness and tolerability of Brivaracetam in pediatric patients with epilepsy.

Authors' Contribution
A. R. was the key member of the clinical team, he had full access to all research data, was in charge of confirming the integrity of data and the accuracy of the data analysis, and wrote the manuscript. V. C.
had full access to all research data, was in charge of confirming the integrity of data and the accuracy of data analysis, and wrote the manuscript. L. B., P. B., A. D., and A. P. revised the first draft of the manuscript. G. G. codesigned the study and discussed the interpretation of the data. All authors contributed, read, and approved the manuscript.